Abstract PROBLEM: Most, if not all, cancers depend on the formation of new blood vessels (angiogenesis) for growth and progression. Therapeutic intervention strategies targeting angiogenesis are beginning to show promise, but unfortunately, the disease eventually progresses because the tumor cells find a way to bypass the blocked pathway (e.g., by increased secretion of an alternative pro-angiogenic factor). A therapeutic approach that targets multiple pro-angiogenic signals simultaneously would offer a tremendous advantage. PRELIMINARY DATA: The specific functions of STAT (signal transducers and activators) proteins in angiogenesis are currently unknown. Preliminary data from our laboratory indicate that in brain endothelial cells, FGF2, FGF8, and VEGF activate STAT5 and STAT1 but not STAT3. Using constitutively active and dominant negative STAT5 mutants, we determined that STAT5 specifically mediates FGF-induced endothelial cell migration, invasion, and tube formation but not mitogenesis. HYPOTHESIS: STATs mediate critical angiogenic events downstream of several potent mediators. As integration points of multiple signaling pathways, STATs represent anti-angiogenic targets of opportunity. STUDY DESIGN: This hypothesis will be tested by pursuing the following specific aims: Aim 1: Characterize STATs as mediators of pro-angiogenic factors. We will determine the pattern of STAT activation in microvascular endothelial cells in response to FGF2 and VEGF. The specific involvement of STATs in angiogenic responses will be analyzed. The role of STATs in downstream signaling of FGF receptors will be dissected in detail. Aim 2: Determine the role of STATs in vivo and evaluate their utility as therapeutic targets. The role of STAT5 in angiogenesis will be determined in vivo using a genetic approach. The endothelial cell-specific ablation of STATs in animals will be accomplished using the Cre-lox approach. STAT inhibition with small molecules in vivo will provide proof-of-principle support for novel therapeutic intervention strategies. The role of STAT activation in human disease will be determined by analyzing human tumor samples. POTENTIAL IMPACT ON VETERANS' HEALTH CARE: The number of annual deaths from cancer has recently surpassed the number of deaths from cardiovascular disease. This disturbing statistical fact underscores the magnitude of the cancer threat. The advanced average age of veterans predisposes this population group to a multitude of malignancies. Novel therapeutic strategies that target tumor angiogenesis in a variety of tumor types and circumvent mechanisms of resistance development would be highly desirable. This is important work aimed at understanding an understudied molecule with the potential for high payoff for the veteran population. PUBLIC HEALTH RELEVANCE: Relevance Statement Deaths from cancer have recently surpassed deaths from heart disease and stroke. Cancer incidence increases with age, and therefore, cancer represents a major health problem for the US population as a whole and especially veterans. This threat to health and life is particularly evident in the case of brain tumors and lung cancer, the focus points of this proposal. Brain tumors are not very common, but they are counted among the deadliest cancers in humans. Lung cancer is both common and lethal. We urgently need more effective treatments for these and other cancer types. Cancerous tumors depend on the formation of new blood vessels (angiogenesis) for growth and progression. Cancer cells secrete factors that recruit blood vessels from the surrounding tissue. Therefore, it appears plausible that targeting blood vessel growth could be an effective cancer treatment approach. Recent clinical trials show that drugs designed to inhibit a vessel-inducing factor slow down tumor growth and prolong survival. Unfortunately, the tumor eventually resumes its relentless growth and kills the patient. Laboratory evidence indicates that tumors adapt during treatment and secrete alternative vessel stimulating factors - effectively bypassing the therapeutic block. If one could find a way of blocking several vessel-stimulating pathways simultaneously, resistance development might be prevented, and a breakthrough in cancer therapy might be achieved. Unfortunately, universal drug targets in tumor vessels are currently unknown. Our research indicates that the STAT proteins might be such targets. We found that STATs are activated by several critical vessel-inducing factors. In the lab, blocking STATs disrupts vessel formation. We propose to study STATs in detail to understand their function and to explore their usefulness as a treatment target. As part of this project, we will test inhibitors of STATs that have recently become available. If effective, STAT inhibitors could be used to treat not only brain and lung tumors, but a variety of cancers, improving the lives of US veterans.